L13-L14 Epilepsy Flashcards
Compared with the general population, the risk of premature death amongst people with epilepsy is _____.
Increased 2- to 3- fold
Highest w/in 1st 12 months of diagnosis
List all epilepsy-related mortality risk factors.
1) Sudden unexplained death in epilepsy patients (SUDEP)
2) Status epilepticus
3) Unintentional injuries (e.g. drowning, head injuries, burns) during episodes
4) Suicide
Explain what “SUDEP” means.
Sudden unexplained death in epilepsy patients
1) Incidence: 1-2 per 1000 person-years
- Peak: 20-40 y/o
2) Mostly unwitnessed and sleep-related
- Many individuals w/ SUDEP are found in prone position w/ evidence of having had a recent seizure.
- Rare cases occurring during video electroencephalogram (EEG) monitoring suggests that SUDEP is preceded by a convulsion followed shortly w/ apnoea (i.e. cessation of breathing) then asystole (i.e. cessation of electrical & mechanical activity of the heart)
What are some risk factors that may lead to the occurrence of SUDEP in epileptic patients?
1) Presence & frequency of generalised tonic-clonic seizures
2) Nocturnal seizures
3) Lack of seizure freedom
Based on the ILAE guidelines, differentiate between seizure and epilepsy.
Seizure:
Transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain
Epilepsy:
Disease of the brain defined by ANY of the following conditions:
1) At least 2 unprovoked seizures occurring > 24h apart
2) One unprovoked seizure AND a probability of further seizures similar to general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years
3) Diagnosis of an epilepsy syndrome
- Conceptually, epilepsy is a brain disorder characterised by an enduring predisposition to generate epileptic seizures.
What are some differential factors that help distinguish if a seizure is provoked or unprovoked?
STIIM:
- Interval between insult & seizure may vary according to the underlying condition.
1) Structural: Traumatic brain injury & stroke (scar formation in brain)
2) Toxic substance/drugs:
- Illicit drugs (e.g. cocaine, amphetamines)
- Drugs (e.g. TCAs, carbapenems)
- Alcohol withdrawal & intoxication
- BZDs (abrupt) withdrawal
3) Infections:
4) Inflammation
- CNS infection (e.g. neurosyphillis, meningitis, enchepalitis)
- Febrile illlnesses
5) Metabolic (including electrolyte imbalances):
- Hyponatremia
- Hypokalemia
- Hypomagnesemia
- Hypoglycemia
Explain the pathophysiology leading to a seizure episode.
Key Concepts: Hyperexcitability & Hypersynchronisation
- Instability in a single neuronal cell membrane or group of cells around it
- Characterised by synchronised paroxysmal discharges occurring in a large population of neurons w/in cortex.
1) Hyperexcitability: Enhanced predisposition of a neuron to depolarise due to…
- Abnormalities in Na+, K+, Ca2+ and Cl- ions in ICF & ECF across voltage-gated Na+, K+, Ca2+ and Cl- ion channels
- Excessive excitatory neurotransmitters (e.g. glutamine, acetylcholine, histamines, cytokines etc.)
- Insufficient inhibitory neurotransmitters (e.g. GABA, dopamine)
2) Hypersnychronisation:
- Intrinsic organisation of local circuits (i.e. hippocampus, neocortex & thalamus) contribute to synchronisation and promote generation of epileptiform activity.
List the various etiologies of epilepsy.
1) Genetic
2) Structural: Traumatic brain injury, tumours, hypoxic-ischemic abnormalities, vascular malformation
3) Metabolic: Mitochondrial disorders, glucose transporter 1 (GLUT1) deficiency
4) Immune: Ab mediated
5) Infection: Bacterial meningitis, HIV, meningo-TB
6) Unknown
Explain how the various types of epilepsy are classified.
Based on mode of onset:
1) Focal onset: Seizures ONLY in one hemisphere
- May spread to contralateral hemisphere i.e. focal seizures evolving to bilateral convulsive seizures
2) Generalised onset: Seizures begin in BOTH hemispheres
AND Based on impairment of consciousness:
- Loss of awareness of external stimuli or inability to respond to external stimuli in a purposeful & appropriate manner
- Described as “with or without dyscognitive features”
What significance does the classification of seizures under ILAE guidelines have in the Tx of epilepsy?
Fundamental characteristic by which to classify seizures helps in identifying treatment & prognostic implications.
Based on the ILAE 2017 Classification of Seizure Types, what key features were used as basis of classifying the various types of epilepsy?
Based on THREE key features:
1) Mode of onset / where seizures begin in the brain
2) Level of awareness during seizure episodes
3) Other features of seizures
Redefine “simple partial seizures” appropriately using the updated terminology in ILAE.
Focal onset seizures without dyscognitive features
Redefine “complex partial seizures” appropriately using the updated terminology in ILAE.
Focal onset seizures with dyscognitive features
What are the factors affecting the clinical characteristics of a seizure?
1) Site of focus
2) Degree of ‘irritability’ of the areas of the brain surrounding the focus
3) Intensity of impulse
Describe the typical clinical presentation of a patient diagnosed with a FOCAL onset seizure WITHOUT dyscognitive features.
1) Motor Symptoms:
- Clonic (i.e. twitching or jerking) movements of the arm, shoulders, face & leg
- Speech arrest / Dysartharia (i.e. involving muscles of articulation)
2) Sensory Symptoms:
- Tingling or feelings of numbness
- Visual disturbances (e.g. flashing lights)
- Rising epigastric sensation
3) Autonomic Symptoms:
- Sweating, salivation or pallor
- Increased BP & HR
4) Somatosensory / Psychic Symptoms:
- Flashbacks, deja vu memories
- Visual, auditory, olfactory & gustatory hallucinations
- Affective symptoms include fear (most common), depression, anger & irritability
Describe the typical clinical presentation of a patient diagnosed with a FOCAL onset seizure WITH dyscognitive features.
1) Aura / Somatosensory / Psychic Symptoms:
- Manifestations as described in focal non-dyscognitive features seizures
- Usually last for a few seconds
- i.e. Flashbacks, deja vu memories
- Visual, auditory, olfactory & gustatory hallucinations
- Affective symptoms include fear (most common), depression, anger & irritability
2) Impaired consciousness: Amnesia to event
3) Automatisms: Lip smacking, chewing, repetitive speech, picking at their clothes unpurposefully
Describe the typical clinical presentation of a patient diagnosed with a GENERALISED onset tonic-clonic seizure.
Most common & best known type; also known as “grand mal”.
Begins w/ stiffening of limbs (tonic phase), followed by jerking of limbs and face (clonic phase)
1) Tonic Phase:
- Begins w/ stiffening of limbs
- Breathing may decrease or cease altogether
- Cyanosis of nail beds, lips & face
2) Clonic Phase:
- Followed by jerking of limbs & face after tonic phase
- Reversal of cyanosis typically in clonic phase but may be irregular
- Usually lasts for 1 min, after which brain is extremely hyperpolarised & insensitive to stimuli
- Incontinence may occur, along with biting of tongue or inside of mouth
- Breathing may be noisy & appeared to be laboured
3) Post-Seizure:
- Following seizure episode, pt may have HA & appeared lethargic, confused & sleepy
- Full recovery takes several minutes to hours
Describe the typical clinical presentation of a patient diagnosed with a GENERALISED onset clonic seizure.
Clonic jerking often asymmetrical & irregular
Clonic seizures are most frequent in neonates, infants or young children.
Describe the typical clinical presentation of a patient diagnosed with a GENERALISED onset tonic seizure.
Sudden loss of consciousness & rigid posture of entire body that last 10-20 seconds
- Occur at all ages in setting of diffuse cerebral damage & learning disability
- Invariably associated with other seizure types
- Characteristics & defining seizure type in Lennox-Gastaut syndrome
Describe the typical clinical presentation of a patient diagnosed with a GENERALISED onset absence seizure.
Known as “petit mal” seizures in literature.
1) Usually manifests as basic lapse in awareness that begins & ends abruptly.
- Sometimes mistaken as persistent staring
- Lasts ONLY a few seconds W/O warning W/O after-effects
- Often undetected even if there are 50-100 attacks/day
2) 1st onset: Usually 4-12 y/o; rarely after 20 y/o
- More common in children than in adults
3) Absence seizures DIFFER from complex partial seizures in that they:
- NEVER preceded by auras
- last SECONDS (rather than minutes)
- begin FREQUENTLY & end ABRUPTLY
- produce CHARACTERISTIC EEG pattern “3Hz spike waves”
- May be mistaken for complex partial seizures, resulting in wrong choice of medication prescribed.
Describe the typical clinical presentation of a patient diagnosed with a GENERALISED onset atonic seizure.
Most SEVERE form is the classic drop attack (astatic seizure) in which all postural tone is suddenly lost, causing collapse to the ground like a rag doll
- Short episode & followed by immediate recovery
- Occur at any age & are always associated w/ diffuse cerebral damage & learning disability
- Common in severe symptomatic epilepsies (esp. in Lennox-Gastaut syndrome & in myoclonic-astatic epilepsy)
What are the laboratory tests and investigations that are used in the diagnosis and management of seizures?
1) Thorough Hx-taking is impt.:
- Description of onset, duration & characteristics of a seizure
- Accurate Hx best provided by person who has observed events
- Pt. is useful in describing details of auras, preservation of consciousness & post-ictal/post-seizure state
2) Neurological examinations:
- Scalp electroencephalography (EEG)
- Video EEG
- Magnetic resonance imaging (MRI) w/ gadolinium
3) Biochemical / Toxicology lab exams
4) Concomitant medical conditions
What are some classical characteristics that positively identifies a patient experiencing symptoms of epilepsy?
- Aura
- Cyanosis
- Loss of consciousness
- Motor manifestations
- Generalised stiffness of limbs & body
- Jerking of limbs
- Tongue biting
- Urinary incontinence
- Post-ictal/seizure confusion
- Muscle soreness
What are some differential diagnoses to exclude before identifying one has epilepsy?
Syncope: “fit” (seizures) vs “faint” (syncope) dilemma
Transient ischaemic attack
Migraine
Psychogenic nonepileptic seizures
Describe how the scalp EEG helps in the diagnosis of epilepsy.
Essential tool for diagnosis & classification of seizures & epileptic syndromes
- Epileptiform discharges on EEG CONFIRM diagnosis
- However, a normal EEG does NOT exclude possibility of epilepsy
What are the limitations of using scalp EEG to help in the diagnosis of epilepsy?
1) NOT all epileptic patients have an abnormal EEG.
- 50% chance of showing epileptiform activity in a first awake EEG.
- 80-90% sensitivity w/ repeated awake-sleep EEGs.
2) EEG can be abnormal in normal persons
- False-positive epileptiform discharges on EEG in asymptomatic adults = 0.5-1%
Describe how the video EEG helps in the diagnosis of epilepsy.
Increasingly being used in diagnosis in pt w/ suspected psychogenic non-epileptic seizures (PNES)
If matching epileptic EEG w/ actual video evidence shows manifestations of seizure event, it is a good indicator to diagnose if indeed is an unprovoked seizure.
Describe how the MRI w/ gadolinium helps in the diagnosis of epilepsy.
Ordered for adult pt who presents w/ 1st seizures, pt w/ focal neurological deficits or suggestion of focal onset seizure.
Helps in the identification of focal lesions:
- Mesial temporal sclerosis
- Focal cortical dysplasia
- Remote injury (old stroke etc)
- Tumor
- Vascular malformation
Describe how the biochemical / toxicology investigations help in the diagnosis of epilepsy.
Helps to rule out electrolyte abnormalities
Creatinine kinase is usually raised after generalised tonic-clonic seizure episode.
Serum prolactin can be used routinely as a biochemical marker to diagnose patients with epilepsy. True or false?
False.
Considerable variability & NOT used routinely.
Describe the algorithm in determining whether a patient has epilepsy upon first seizure.
1) Was it a seizure?
2) Was it the first seizure?
3) Was it a provoked seizure?
4) If not, what is the likely etiology?
5) Does the patient need anti-seizure medications (ASM)?
- What is the risk of seizure recurrence?
- Patient factors
- Which ASM?
How do we determine the risk of seizure recurrence?
1) Risk of second seizure:
- ~30% w/in next 5 years, higher in first 2 years
- Higher in presence of:
(a) Epileptiform EEG
(b) Prior brain insult (i.e. stroke, trauma)
(c) Structural abnormality in brain imaging
(d) Noctural seizure
2) Risk of recurrent seizures after two unprovoked seizures at 4 years = 70%
What are some considerations before starting on ASM?
Considerations:
1) Recurrence risk:
- Treatment after 1st seizure can reduce risk of 2nd seizure
- However, no effect on long-term prognosis.
- No evidence of higher risk of death, injuries or status epilepticus in pt allocated to deferred Tx in FIRST & MESS studies
2) Potential seizure morbidity
3) Risk of Tx
4) Personal circumstances
Key Determinants:
1) Cause, epilepsy syndrome, EEG findings
2) Seizure types
3) Tolerability
4) Work, need for drive license, desire to bear children
DO NOT START Tx when pt isn’t at high risk (i.e. > 60%)!!
What are the therapeutic goals in the treatment of epilepsy?
1) Absence of epileptic seizures
2) Absence of ASM-related side effects
3) Attainment of optimal QoL
About 2/3 of pt are able to achieve seizure freedom.
Non-pharmacological options are the mainstay in the Tx of epilepsy. True or false?
False.
Pharmacological Tx is the mainstay, while non-pharmacological options are adjunctive.
What are some non-pharmacological options a pt w/ epilepsy may consider adopting?
1) Ketogenic diet
2) Lifestyle modifications: Seizure diary & avoid preventable seizure triggers where possible
3) Vagus nerve stimulation (VNS)
4) Responsive neurostimulator system (RNS)
5) Surgery
Treatment strategy for epilepsy should be individualised according to:
1) Seizure type and/or epilepsy syndrome:
- Whether rapid titration is required
- E.g. lamotrigine & topiramate requires slow titration; carbamezapine undergoes autoinduction
2) Co-medications & comorbidities:
- Migraine: Consider topiramate, valproate
- Depression/Anxiety: Use levetiracetam w/ caution
- DDI: Caution for pt on HIV medications & immunosuppressants
- Route of elimination i.e. Hepatic / renal impairment
- Special population: Consider levetiracetam / lamotrigine & AVOID valproate for women w/ childbearing potential
3) Pt’s lifestyle & preferences:
- Dosage form & dosing frequency
- Lifestyle & occupational considerations
4) National / Institutional:
- Guidelines
- Availability
- Costs & financial subsidies
What are the general principles driving the selection of pharmacological treatment of epilepsy?
1) Monotherapy preferred:
- Likely lower incidence of adverse effect
- Absence of DDI
- Reduced risk of birth defects
- Lower cost
- Easier to correlate response & adverse effects
- Better adherence
2) Tx Initiation: Start w/ low dose of 1st line ASM appropriate for particular seizure type
- If seizures continue BUT no side effects, gradually increase dose of ASM
- If seizures continue despite maximum tolerated dose of 1st line ASM:
(a) Review diagnosis
(b) Ensure appropriate drug for seizure type / epileptic syndrome
(c) Check adherence
3) Failure of 1st line Tx of ASM:
- Chances of seizure freedom after failure of 1st ASM is low = 16%; may require combination (adjunctive) Tx
- No consensus / sufficient evidence / validated algorithm to support substitution monotherapy or combination Tx
- Substitution: Consider if 1st ASM produces ADR & not tolerated at low doses / does not improve seizures
- Combination Tx: Consider if pt tolerates 1st or 2nd ASM BUT w/ suboptimal response
What are some factors to consider when combining ASMs for pharmacological Tx of epilepsy after the failure of 1st line ASM?
1) Previous clinical response of patient to each drug alone
2) ASM’s MOA
3) ASM’s tolerability profile
4) ASM’s PK profile
About _____ of patients w/ new onset focal or generalised seizures achieve _____ while taking the ______ 1st line antiepileptic drug.
50%
Seizure freedom
Initial appropriately selected & dosed
About _____ of patients have drug resistant epilepsy, which is defined as failure of adequate trials of _____, _____ & _____ to achieve sustained seizure freedom.
30%
TWO tolerated, appropriately chosen & used antiepileptic drug schedule
Describe how the ketogenic diet is used as a non-pharmacological Tx option for epileptic patients.
1) Used in patients who cannot tolerate or have NOT responded well to ASM treatment.
- Used mainly in young children (evidence) to prevent seizures
2) Comprises of low carbohydrate, high-fat diet to induce ketosis.
- Aim to change how the brain uses energy (from carbohydrates to ketones) to function, though MOA is not well understood.
- Challenging to adhere long-term
Describe how the vagus nerve stimulation is used as a non-pharmacological Tx option for epileptic patients.
Indicated ONLY for intractable focal seizures
- Electrodes attached around left branch of vagus nerve as well as well as connected to programmable stimulator
- Stimulator delivers cyclical stimulation
- During a seizure, ‘on-demand’ stimulation can be achieved by placing a magnet next to SC-implanted stimulator
Describe how the responsive neurostimulator system is used as a non-pharmacological Tx option for epileptic patients.
New adjunctive therapy to help reduce the frequency of partial-onset seizures in pt who have:
- Undergone diagnostic testing that localised at most TWO epileptogenic foci
- Refractory to at least TWO ASMs
- Frequent & disabling symptoms
RNS continuously monitors electrical activity in the brain, detects patient-specific patterns & delivers brief pulses of stimulation when it detects activity that could lead to a seizure.
